TY - JOUR
T1 - DNA methylation of telomere-related genes and cancer risk
AU - Joyce, Brian T.
AU - Zheng, Yinan
AU - Nannini, Drew
AU - Zhang, Zhou
AU - Liu, Lei
AU - Gao, Tao
AU - Kocherginsky, Masha
AU - Murphy, Robert
AU - Yang, Hushan
AU - Achenbach, Chad J.
AU - Roberts, Lewis R.
AU - Hoxha, Mirjam
AU - Shen, Jincheng
AU - Vokonas, Pantel
AU - Schwartz, Joel
AU - Baccarelli, Andrea
AU - Hou, Lifang
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/8
Y1 - 2018/8
N2 - Researchers hypothesized that telomere shortening facilitates carcinogenesis. Previous studies found inconsistent associations between blood leukocyte telomere length (LTL) and cancer. Epigenetic reprogramming of telomere maintenance mechanisms may help explain this inconsistency. We examined associations between DNA methylation in telomere-related genes (TRG) and cancer. We analyzed 475 participants providing 889 samples 1 to 3 times (median follow-up, 10.1 years) from 1999 to 2013 in the Normative Aging Study. All participants were cancer-free at each visit and blood leukocytes profiled using the Illumina 450K array. Of 121 participants who developed cancer, 34 had prostate cancer, 10 melanoma, 34 unknown skin malignancies, and 43 another cancer. We examined 2,651 CpGs from 80 TRGs and applied a combination of Cox and mixed models to identify CpGs prospectively associated with cancer (at FDR < 0.05). We also explored trajectories of DNA methylation, logistic regression stratified by time to diagnosis/censoring, and cross-sectional models of LTL at first blood draw. We identified 30 CpGs on 23 TRGs whose methylation was positively associated with cancer incidence (b ¼ 1.0–6.93) and one protective CpG in MAD1L1 (b ¼ 0.65), of which 87% were located in TRG promoters. Methylation trajectories of 21 CpGs increased in cancer cases relative to controls; at 4 to 8 years prediagnosis/censoring, 17 CpGs were positively associated with cancer. Three CpGs were cross-sectionally associated with LTL. TRG methylation may be a mechanism through which LTL dynamics reflect cancer risk. Future research should confirm these findings and explore potential mechanisms underlying these findings, including telomere maintenance and DNA repair dysfunction.
AB - Researchers hypothesized that telomere shortening facilitates carcinogenesis. Previous studies found inconsistent associations between blood leukocyte telomere length (LTL) and cancer. Epigenetic reprogramming of telomere maintenance mechanisms may help explain this inconsistency. We examined associations between DNA methylation in telomere-related genes (TRG) and cancer. We analyzed 475 participants providing 889 samples 1 to 3 times (median follow-up, 10.1 years) from 1999 to 2013 in the Normative Aging Study. All participants were cancer-free at each visit and blood leukocytes profiled using the Illumina 450K array. Of 121 participants who developed cancer, 34 had prostate cancer, 10 melanoma, 34 unknown skin malignancies, and 43 another cancer. We examined 2,651 CpGs from 80 TRGs and applied a combination of Cox and mixed models to identify CpGs prospectively associated with cancer (at FDR < 0.05). We also explored trajectories of DNA methylation, logistic regression stratified by time to diagnosis/censoring, and cross-sectional models of LTL at first blood draw. We identified 30 CpGs on 23 TRGs whose methylation was positively associated with cancer incidence (b ¼ 1.0–6.93) and one protective CpG in MAD1L1 (b ¼ 0.65), of which 87% were located in TRG promoters. Methylation trajectories of 21 CpGs increased in cancer cases relative to controls; at 4 to 8 years prediagnosis/censoring, 17 CpGs were positively associated with cancer. Three CpGs were cross-sectionally associated with LTL. TRG methylation may be a mechanism through which LTL dynamics reflect cancer risk. Future research should confirm these findings and explore potential mechanisms underlying these findings, including telomere maintenance and DNA repair dysfunction.
UR - http://www.scopus.com/inward/record.url?scp=85050997064&partnerID=8YFLogxK
U2 - 10.1158/1940-6207.CAPR-17-0413
DO - 10.1158/1940-6207.CAPR-17-0413
M3 - Article
C2 - 29895583
AN - SCOPUS:85050997064
SN - 1940-6207
VL - 11
SP - 511
EP - 522
JO - Cancer Prevention Research
JF - Cancer Prevention Research
IS - 8
ER -